Helplessness, a behavioral state of passivity with feelings of uncontrollability, is a common component of depression and post-traumatic stress disorder (PTSD). Even though stress plays a well-understood role in these disorders, there is a need to investigate congenital (inborn) neurobiological predispositions that underlie the helplessness trait, because only a minority of people develops depression or PTSD following stress or trauma. The broad objective of the proposed research is to better understand how congenital predisposition alters brain and behavior by studying the congenitally helpless rat - a selectively bred strain which shows the helplessness trait. The first aim is to further characterize this model behaviorally with separate tests in adult rats to ascertain whether congenitally helpless rats show a temperamental profile resembling individuals susceptible to PTSD: high exploration in novel environments, low reward sensitivity, and an exaggerated response to fear-evoking stimuli. The second aim is to metabolically map the brains of naive congenitally helpless rats at critical developmental stages in order to identify the underlying brain alterations. It is anticipated based on preliminary data that brains of newborn congenitally helpless rats will show innate reductions in interregional correlations of brain activity, particularly between forebrain and brainstem regions. This congenital alteration may subsequently impair feedback to the hypothalamic-pituitary-adrenal (HPA) axis. The third aim is to map the effects of the antidepressant fluoxetine on the brains of congenitally helpless rats. It is hypothesized that fluoxetine antidepressant effects may be mediated by decreasing metabolism in the lateral habenula. The habenula may provide a major modulatory influence on the HPA axis through its inputs to septohippocampal and monoaminergic systems. Brain metabolic effects will be evaluated with quantitative histochemistry of cytochrome oxidase because this method offers important advantages for mapping changes in neurobiological predispositions. Cytochrome oxidase is unique in that it marks cumulative, long-term neuronal activity, thus making it ideal for assessing baseline brain differences in animals from different genetic strains and in response to chronic antidepressant administration. Greater knowledge of brain mechanisms underlying the congenital predisposition to helplessness would be beneficial to develop more effective treatments for affective disorders.